Cigarette smoking poses one of the most daunting public health challenges in the United States and abroad. About one fourth of Americans smoke cigarettes, and while a majority of smokers express a desire to quit, few are successful at maintaining abstinence over a one-year period. Accumulating evidence now suggests that genetic factors play an important role in this persistent smoking. In particular, some, but not all, studies have demonstrated that smokers who are less successful at quitting are significantly more likely to carry polymorphisms in genes related to the CNS dopamine signaling pathway, conferring increased dopamine sensitivity ("risk polymorphisms"). The underlying biobehavioral mechanisms linking these polymorphisms to persistent smoking behavior are not yet known. One possibility is suggested by initial results from our lab looking at two specific risk polymorphisms. Smokers carrying these polymorphisms exhibited heightened cigarette craving after experimental exposure to an imaginal stressor (dental imagery). Generalizability to other stressors, though, has yet to be demonstrated. Based on these initial findings, we propose to test a biobehavioral model in which carriers of risk polymorphisms have stronger craving reactions to stress, which, in turn, relate to poorer cessation success. Clinical reports have also raised the possibility that women's stress-induced cravings for cigarettes are particularly strong, as compared to men. Preliminary evidence from our lab has confirmed that women had stronger stress-induced craving responses than men. Another exploratory goal of this project is, thus, to examine the possibility that women, and particularly those carrying the polymorphisms under investigation, will have stronger craving reactions to stress. The research proposed in this 3-year K22 application focuses on three specific aims: Aim 1: To investigate the possibility that carriers of risk polymorphisms display stronger craving reactions to stressors than non-carriers, using a controlled laboratory model of stress-induced craving. Former and current smokers (n=216; 50% men, 50% women) will be genotyped and assessed by self-report and cardiovascular monitoring before, during, and after imaginal and in-vivo exposures to stressors. Aim 2: To examine the possibility that stress-induced craving reactions will be associated with smoking cessation success, using a case-control analysis. Stress- induced craving reactions in former and current smokers (n=108/group), matched by demographics and smoking habits, will be compared. Aim 3: To test the overall proposed biobehavioral model, in which risk polymorphisms predict stress-induced craving, which in turn contributes to cessation success in combined hierarchical logistic regression models and path analyses. Results will set the stage for the development of innovative smoking cessation strategies to reduce the personal and public health burden of smoking.